Rare t(X;14)(q28;q32) translocation reveals link between MTCP1 and chronic lymphocytic leukemia

Rare, recurrent balanced translocations occur in a variety of cancers but are often not functionally interrogated. Balanced translocations with the immunoglobulin heavy chain locus (IGH; 14q32) in chronic lymphocytic leukemia (CLL) are infrequent but have led to the discovery of pathogenic genes including CCND1, BCL2, and BCL3. Following identification of a t(X;14)(q28;q32) translocation that placed the mature T cell proliferation 1 gene (MTCP1) adjacent to the immunoglobulin locus in a CLL patient, we hypothesized that this gene may have previously unrecognized importance. Indeed, here we report overexpression of human MTCP1 restricted to the B cell compartment in mice produces a clonal CD5+/CD19+ leukemia recapitulating the major characteristics of human CLL and demonstrates favorable response to therapeutic intervention with ibrutinib. We reinforce the importance of genetic interrogation of rare, recurrent balanced translocations to identify cancer driving genes via the story of MTCP1 as a contributor to CLL pathogenesis.

longer MTCP1 isoform is a member of the TCL1 proto-oncogene family and is amplified in t(X;14)associated T cell leukemia.
(b) 3-Dimensional surface rendering with beta-barrel tertiary structures as determined via crystal structure analysis showing high degree of overlap between human p13 MTCP1 and p14 TCL1A (RCSB IDs: 1A1X, 1JSG). Surface residues Asp16, Ile74, and Ser89 have shown to be critical for TCL1A-AKT interactions, and biochemical conservation of these residues on the surface of p13 MTCP1 (Asp12, Leu68, Ser83) suggests shared AKT-binding abilities between family members.
Space fill rending of these conserved amino acid residues possibly necessary for AKT interactions are highlighted.
Representative survival of wildtype mice (n=54) is shown as reference. P-values (in b and c) determined by estimates from a Cox proportional hazards model.
(d) Competing-risk assessment to estimate the median survival in Eµ-MTCP1 (Z36 and Z20) and Eµ-TCL1 mice. Mice were censored (black mark on curve) at the time at which a T cell or myeloid cell abnormality were observed. The median estimated survival time was 12.4 months for Eµ-MTCP1 found Z36 (n=54) and 17.6 months for Eµ-MTCP1 founder Z20 (n=36). The Median estimated survival for Eµ-TCL1 mice was 14.1 months (n=33). "***" represents p<0.001 and "*" represents p=0.0503 using a two-tailed unpaired t-test with Welch's correction.
(e) Evaluation of time between CLL onset (defined in b) and time of death in Eµ-MTCP1 (Z36, n=38; Z20, n=10) and Eµ-TCL1 (n=32) mice. Reduced time from disease onset to death reflects the delayed onset but rapid disease course in Eµ-MTCP1 mice. "***" represents p<0.001 using a twotailed unpaired t-test with Welch's correction.  ---A Stratified on study cohort. B Each predictor is adjusted for all others in the model. HR = hazard ratio, CI = confidence interval P-values are from two-sided t-tests, obtained from stratified Cox proportional hazards models combined across 20 imputed datasets. P-values were not adjusted for multiple testing. Each predictor is adjusted for all others in the model. HR = hazard ratio, CI = confidence interval P-values are from two-sided t-tests, obtained from stratified Cox proportional hazards models combined across 20 imputed datasets. P-values were not adjusted for multiple testing.